The overall goal of this SPORE application is to develop more effective targeted molecular therapies and biomarkers for glioblastoma. The four proposed projects focus on 1) Overcoming resistance to VEGF inhibition by targeting Angiopoietin-2; 2) Inhibiting the phosphatidylinositol 3-kinase (PIS kinase) pathway; 3) designing novel strategies for imaging and targeting IDH mutant gliomas; and 4) Increasing the radiosensitivity of glioblastomas by inhibiting the bHLH transcription factor 01ig2. One of the innovative themes of this SPORE proposal is that biospecimens collected by the Pathology Core will be comprehensively molecularly profiled using multiplexed technologies so projects may effectively evaluate the interaction of targeted therapies and their targets. The Pathology Core will support the goals of the SPORE by providing expert neuropathologic review, biospecimen banking and clinical trial support. In addition, the Pathology Core will be a centralized resource for clinically and molecularly annotated glioblastoma tissues and primary glioblastoma cell cultures that will be essential to the success of the proposed projects. By centralizing these activities, the Pathology Core will ensure the safe and effective use of finite glioblastoma tissue resources without limiting the scope of the translational research planned in this proposal. The SPORE support, combined with significant institutional support for these goals, will ensure that over the next 5 years the Pathology Gore will provide the critical research infrastructure required for successful, collaborative translational research of the SPORE program.